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Biomechanical, Microvascular, and Cellular Factors Promote Muscle and Bone Regeneration

Duda, Georg N.; Taylor, William R.; Winkler, Tobias; Matziolis, Georg; Heller, Markus O.; Haas, Norbert P.; Perka, Carsten; Schaser, Klaus-D.

Exercise and Sport Sciences Reviews: April 2008 - Volume 36 - Issue 2 - p 64-70
doi: 10.1097/JES.0b013e318168eb88
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It is becoming clear that the long-term outcome of complex bone injuries benefits from approaches that selectively target biomechanical, vascular, and cellular pathways. The typically held view of either biological or mechanical aspects of healing is oversimplified and does not correspond to clinical reality. The fundamental mechanisms of soft tissue regeneration most likely hold the key to understanding healing response.

Muscles play a role as the primary carrier of "extra-osseous" blood supply AND actuators for restoring biomechanical balance within the musculoskeletal system.

Julius Wolff Institut, Center for Musculoskeletal Surgery and Berlin-Brandenburg Center for Regenerative Therapies Charité-Universitätsmedizin Berlin, Free and Humboldt University of Berlin, Berlin, Germany

Address for correspondence: Georg N. Duda, Ph.D., Julius Wolff Institut, Center for Musculoskeletal Surgery and Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, D-13 353 Berlin, Germany (E-mail: georg.duda@charite.de).

Accepted for publication: December 10, 2007.

Associate Editor: Walter Herzog, Ph.D.

Georg N. Duda and William R. Taylor share first authorship.

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INTRODUCTION

Restoration of balanced musculoskeletal loading conditions during surgical correction of bones and joints is critically reviewed; pointing out that overcorrection may cause even more demanding mechanical conditions than those originally leading to surgery. In this context, the role of muscle activity in loading-injured extremities has been analyzed. The findings demonstrate that partial weight bearing cannot be considered an effective modality for reducing loading in a healing musculoskeletal structure. In illustrating the interaction of joint degeneration and muscle activity, the role of muscles as the predominant contributor of mechanical stimuli, both in tissue hemostasis and during tissue healing and regeneration, becomes strikingly evident. As a consequence, damage to skeletal muscles or the periosteum, is long lasting and plays a crucial role in the healing process of bones, not only for biological, but also for mechanical, reasons.

The goal of this review is to foster a discussion between researchers from the fields of physiology, biology, orthopedic research, and clinicians focusing on trauma, regeneration, and reconstruction of musculoskeletal tissues. It is our hypothesis, based upon a research and a clinical perspective, that skeletal muscles and bones must be considered as a functional unit with biological and mechanical interactions at many levels, such as vascular supply, mechanical stability, and cellular exchange. We also propose that the extraosseous soft tissues, as the primary carrier of the bone's blood supply, serve as protectors of bone and as actuators for restoring biomechanical balance within the musculoskeletal system.

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THE ROLE OF MUSCLES IN LOADING OF INTACT LONG BONES: GENERAL CONSIDERATIONS

Based on validated analyses of hip contact forces, a musculoskeletal model was used to determine the loading conditions within the proximal femur (2,11). Generally, the intact femur showed large compressive forces with relatively small shear forces during normal everyday loading conditions. The compression and shear forces increased from the diaphyseal toward the metaphyseal region during walking. This situation is certainly related to the insertion sites of the muscles that cross the joints and the relatively large activity of the abductors. During stair climbing of healthy individuals, the forces on the femur showed a peak in the diaphysis caused by the activity of the vasti. In general, bending moments outweighed torsional forces and showed a maximum within the diaphysis. Overall, the femoral bending moments, determined based on the analysis of musculoskeletal loading, were considerably smaller than those obtained previously when muscle forces were neglected (10).

For locomotion activities, femoral loading was primarily compressive with minor shear forces (Fig. 1). The load magnitude varied between activities and between trials of the same activity in a given individual. The highest hip joint contact forces occurred during stair climbing in all four individuals tested (2) and were related to the high knee flexion angles. In general, the forces and moments during stair climbing were considerably higher than those during level walking. However, for really fast walking conditions, we measured hip contact forces that were higher than those measured during stair climbing (3). The differences between walking and stair climbing illustrate the variability of femoral loading conditions for different activities, and although the general ratio of compression to shear forces and bending to torsional moments remained similar for all locomotion conditions, the loading magnitude and patterns varied to some degree because of differences in muscular activity.

Figure 1

Figure 1

Furthermore, we measured excessive hip contact forces for specific uncoordinated activities such as accidental stumbling (4). Based on our limited analyses, it seems that extreme load magnitudes may occur not only within the joint, but throughout the entire femur. Although only few measurements exist that include excessive forces, such as those that occurred during accidental stumbling, the current theoretical analysis of musculoskeletal loading suggests that muscle activity is the primary cause of extreme loading in joints. Aside from the joints, all other bony regions spanned by the activated muscles are loaded excessively. Therefore, regaining stability after accidental stumbling causes high joint loading and extreme compressive, shear, and bending loading of bones, as the muscles are activated at or near maximal levels (7). The potential for fracture, especially in osteoporotic patients, may be connected to the quality and speed of the subject's neuromuscular control mechanisms and therefore their ability to avoid unbalanced and uncoordinated movements.

In recent decades, knowledge regarding the loading of long bones has increased both for clinical evaluation and for the design of experimental setups for biomechanical analysis (14). Over half a century ago, Pauwel's (14) analyses had already demonstrated that a high proportion of the joint contact force is caused by muscles crossing the joint. The loading conditions for the proximal femur have often been represented by the hip contact force alone. This lends support to the notion that forces - coming from the top - are transmitted through the head of the femur and leave the bone at its distal end. This understanding has been used widely in the design of experimental setups, analytical analyses of fatigue testing, testing of primary stability of implants, and remodeling studies. Based on knowledge from in vivo measurements and analysis of musculoskeletal loading, muscles have been shown to be the major contributors to the loading of long bones. Muscles compress bones between their origin and insertion sites and thereby generate the contact forces at joints. The resulting loading environment is therefore generally composed of local regions of high compression (near the joints) with lower forces in the diaphysis (Fig. 1). Only multijoint muscles actually generate loading that spans the entire length of bones. Consequently, any attempt to understand femoral loading needs to consider the relationship between joint contact forces and muscle forces.

Our studies demonstrated that internal musculoskeletal loading could be estimated from external measurements. Although internal loading varied between patients, activities, and trials, the femur was generally loaded in compression with small shear forces at the epiphyseal and metaphyseal sections. Slight variations in implantation led to considerable changes in musculoskeletal loading. Data obtained via in vivo measurements for a variety of locomotion activities (10) form the basis for a new understanding of musculoskeletal interaction and open the possibility for optimizing implant surgery, bone and soft tissue loading, and trauma surgery.

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RELEVANCE OF EXTERNAL FORCES FOR INTERNAL CONDITIONS DURING MUSCULOSKELETAL HEALING

Based on our understanding of musculoskeletal loading in normal individuals during everyday activities such as walking and stair climbing, we have attempted to unravel the unknown loading conditions of musculoskeletal tissues during healing. To gain insight into the role of soft tissues for bone loading during healing, musculoskeletal loading was determined in patients with demanding musculoskeletal deficits. Our goal was to quantify the loading at sites of bone defects for selected activities, such as partial weight bearing. Six patients with a segmental bone defect resulting from a complex tibia correction osteotomy participated in this study (6). To obtain reproducible measurements of the loading at the bony fracture site, interfragmentary movements were monitored with reflective markers and infrared cameras (8).

This setup allowed for free mobility of the patients; therefore, the measurements reflected the movements at the healing site during normal activities. The accuracy of the optical system had been validated a priori in an in vitro test (9), and the three-dimensional stiffness of the Ilizarov constructs that were part of the fracture treatment had been previously analyzed in an in vitro study (8,9). Overall, the technical setup and clinical situation were considered appropriate to monitor interfragmentary movements during unrestrained activities. Interfragmentary movements were recorded during muscle cocontraction, standing up, slow walking, and partial weight bearing. Although the patients and treatment interventions varied, the ground reaction forces of the affected limbs were similar among the patients during the initial measurement session (Fig. 2a). The largest load magnitudes and standard deviations were obtained for the walking condition, probably because of the differences in the clinical situation. The variations in interfragmentary motion among patients within a measurement session were small compared with the overall movement magnitude (6). Patients showed small differences in ground reaction forces between resting and cocontraction. Ground reaction forces increased significantly from rest for partial weight bearing, standing up, and walking. Furthermore, ground reaction forces were greater for walking than partial weight bearing. Thus, we considered the partial weight bearing condition as representative for the one prescribed frequently by physicians after trauma to lower limb structures. The affected limbs were loaded more for partial weight bearing than for the cocontraction task.

In contrast to the ground reaction forces, which showed clear differences between the walking, standing up, partial weight bearing, and cocontraction conditions, the interfragmentary movements were similar in axial compression, shear, or twisting around the long axis of the tibia (Fig. 2). No statistically significant differences could be detected between activities, but all activities showed greater interfragmentary movements than the resting condition. The amplitudes of interfragmentary movements during the cocontraction condition illustrate the important role of muscle forces for loading of the healing bone.

Figure 2

Figure 2

Interestingly, partial weight bearing also showed similar interfragmentary movements as those measured for slow walking. This is remarkable insofar as partial weight bearing only produced external ground reaction forces of approximately half the magnitude compared with the slow walking condition. Consequently, interfragmentary motion does not seem to be solely dominated by the external loading of the limb; rather, muscle forces determine the mechanical environment to a great extent and promote the movement of the bone fragments at the site of the defect. This finding is in accordance with statements made previously and with earlier studies in which the importance of muscles for the loading of long bones has been discussed (11,15).

Although interfragmentary movements seem to be largely dominated by muscle activity, the potential influence of external loads cannot be completely excluded. The term "instability," in its traditional meaning in bone fracture research, was introduced to reflect only the interfragmentary conditions independent of the external loads. Instability, therefore, could be considered independent of the ground reaction forces. However, instability data illustrate the importance of muscle activity for loading of the healing fracture zone. In our patient population, partial weight bearing had similar effects on instability at the fracture zone as walking or standing up. Therefore, it seems that partial weight bearing does not unload the healing zone and may represent a false concept in terms of only "partial loading of the internal structures" of the limb (20). Partial weight bearing might be a primarily psychological concept rather than a mechanical device to unload bone healing sites. Nevertheless, in clinical practice, it might help prevent patients from critical situations such as stumbling through an increase in general awareness.

Cocontraction produced instability at the gap more dramatically than partial weight bearing, standing up, and walking, although the latter activities are usually considered more dangerous for overloading the affected limb. The findings in this study, however, demonstrate that simple muscle cocontraction might cause mechanical conditions that are as critical as those occurring during standing up or walking (Fig. 2). In this respect, muscle cocontraction - or even worse - uncontrolled muscle activities, such as those occurring during stumbling, should be avoided because muscular cocontraction (4) likely overloads the healing zone.

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THE IMPORTANCE OF SOFT TISSUE INTEGRITY FOR BONE HEALING

Several studies have investigated the effect of soft tissue trauma on cellular periosteal response (12), skeletal muscle perfusion (16), and fracture healing (19). To date, however, studies aimed at directly visualizing and quantitatively analyzing periosteal microcirculation after closed soft tissue injury (CSTI) are missing. Previous studies have found controversial results regarding the extent of periosteal contribution to diaphyseal/metaphyseal bone circulation. However, there is consensus that the periosteal microvasculature provides the supply and exchange of oxygenated blood, nutrients, and metabolites to the osteogenic cells of the periosteal cambium layer and the cortical bone. Therefore, periosteal microvascular injury, in terms of microvascular disruption, postischemic capillary no reflow phenomenon, and trauma-induced inflammation, is thought to be a key event in the pathophysiology of injury to the bone, that is, fracture (22).

Recent findings from our group suggest that microvascular deteriorations in the periosteum also occur in response to isolated CSTI without a concomitant fracture, as profound capillary and endothelial dysfunction in conjunction with progressive leukocyte activation have been observed. Clinical and experimental studies have started to relate skeletal muscle perfusion to periosteal blood supply and to fracture healing and revealed that skeletal muscle provides an important collateral source of blood to cortical bone. Furthermore, it has been demonstrated that the periosteum and overlying muscles share circulatory channels and have collateral circulation. Thus, soft tissue trauma-induced decrease in nutritional blood flow to the surrounding skeletal muscle may subsequently cause a decline in periosteal microvascular perfusion. This notion is also supported by the finding of decreased capillary blood flow volume at 2 h postinjury, whereas the venular volumetric blood flow tends to increase at that time point. These observations may indicate that part of the blood flow volume usually passing the periosteal capillary bed is temporarily bypassed, or otherwise shunted possibly because of the observed capillary dysfunction (5). Furthermore, the temporal profile of microcirculatory disturbances in the periosteum with persistent capillary derangements, endothelial dysfunction, and leukocyte activation lasting several days indicates rather long-lasting adverse effects of trauma-induced microvascular and inflammatory deteriorations. The increase in venular blood flow volume at 6 wk after trauma varies substantially and may be associated with structural changes of the periosteum and periosteal remodeling processes known to evolve secondary to soft tissue trauma (12).

The involvement of periosteal microvascular derangements in severe CSTI and skeletal muscle microcirculatory dysfunction therefore provides an attractive mechanism by which fractures with severe soft tissue trauma may take longer to heal or even develop a nonunion. However, the response of the periosteum to additional soft tissue trauma does not seem to be uniform, as varying injury severity may induce a different periosteal cellular response. The extent to which decreasing periosteal blood flow and oxygen supply results in osteogenic differentiation and callus formation, and beyond which injury threshold trauma-induced ischemia turns into irreversible ischemic injury and adversely affects fracture healing, however, merits further study. From a clinical perspective, severe concomitant soft tissue trauma has been proposed to precede and causatively underlie perturbed bone healing, frequently resulting in nonunion pseudarthrosis. To date, however, the temporal and functional relationship between skeletal muscle microcirculatory deteriorations and biomechanics of fracture healing after fracture with severe CSTI remains unknown. Using intravital microscopic analysis and biomechanical testing, we quantitatively assessed the impact of microcirculatory disturbances in skeletal muscle after soft tissue damage on fracture healing (18).

In a model of standardized closed tibia fracture in rats, an additional standardized closed soft tissue trauma at the anterolateral tibial compartment was induced using a controlled cortical impact technique (16). Rats in this study were assigned into one of four groups (2 h, 48 h, 1 wk, and 3 wk after the trauma), and the left extensor digitorum longus (EDL) muscle was scanned using in vivo fluorescence microscopy. Biomechanical torsional testing (destructive with intact soft tissue envelope) was performed in rats at 3 and 6 wk after induction of either fracture or fracture with soft tissue trauma. Contrary to homogeneous perfusion in control rats, closed tibial fractures resulted in a significant reduction of functional capillary density and increased microvascular diameter, leukocyte adherence, and macromolecular leakage in the EDL-muscle, indicating trauma-induced inflammation and endothelial disintegration. In comparison, these changes were pronounced 2 h and 48 h after injury in the rats receiving combined fracture and soft tissue trauma. After these fractures with soft tissue trauma, the microvascular deteriorations in skeletal muscle were accompanied by a significantly decreased total failure load and energy absorption in the early fracture healing period (3 wk). Regression analysis between quality of initial capillary perfusion and biomechanical stability (total energy absorption at 3 wk after fracture) revealed a positive relationship. These results suggest that there is an in vivo interaction of soft tissue trauma and fracture healing. It was also shown that initial trauma-induced microcirculatory disturbances and leukocyte activation lead to a significant impairment of early bone healing.

These data further underscore a prognostic significance of the initial microvascular dysfunction in surrounding soft tissue for delayed fracture repair. However, for more detailed and quantitative analysis, future studies are warranted to determine the periosteal callus formation and the biomechanical outcome after fractures with associated severe CSTI. Answers to these questions may result in a better understanding of the mechanisms of periosteal microvascular injury and its effects on bone healing and will likely have an impact on therapeutic management of fractures with severe associated soft tissue injury, involving increased risk of delayed or incomplete fracture healing. Furthermore, adverse effects on the periosteum and bone perfusion are expected to be pronounced by the prolonged manifestation of CSTI-induced microvascular derangements. The delayed course, combined with the continued existence of microcirculatory dysfunction, implicates factors other than trauma for perpetuating the sustained microvascular disturbances and inflammation evolving secondary to CSTI. How this secondary tissue damage after severe CSTI occurs is unclear, but may be attributed to a multitude of changes developing in parallel and sequentially showing a mutual dependency.

Secondary tissue alterations may include skeletal muscle metabolic dysfunction, ongoing degradation of membrane phospholipids, progressive accumulation of free radicals, and inflammation-induced oxidative stress. In addition, a sustained imbalance between vasodilating (e.g., nitric oxide) and vasoconstricting (e.g., endothelins) mediators has been demonstrated, which is thought to result in endothelial cell damage, platelet and leukocyte aggregation, and edema formation (17). Along with these changes, endothelin receptor antagonist treatment has been associated with an improved nutritive perfusion and impaired inflammatory reaction, as significantly increased functional capillary density and decreased leukocyte adherence were observed (21). These beneficial effects form a persuasive base that endothelin is likely to play a causative role in periosteal ischemic tissue injury and that its receptor system may serve as a target for improving periosteal and osseous perfusion.

In conclusion, the data provided by our experimental approach to CSTI offer detailed information on periosteal microvascular response to closed soft tissue trauma. The findings may allow for a temporal correlation of the CSTI-induced individual microvascular derangements in the periosteum and the healing response of fractures with associated soft tissue damage. Thus, these results may have therapeutic implications for preserving periosteal integrity and for considering the interaction of soft tissue damage and periosteal microvascular injury during management of trauma to skeletal muscles and bones.

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MUSCLE REGENERATION: STEM CELLS ENHANCE FUNCTION AFTER SKELETAL MUSCLE INJURY

As muscle regeneration seems to be very important for effective bone healing, it is essential to promote muscle regeneration in parallel with bone regeneration. Our long-term objective is to initiate and promote muscle regeneration especially in critical situations, that is, posttraumatic/ischemic loss of soft tissue, which may exceed the normal regenerative capacity. Thus, methods aimed at stimulating muscle regeneration are of great interest to musculoskeletal rehabilitation researchers. Insufficient posttraumatic skeletal muscle regeneration with associated functional deficiencies continues to be a serious problem in orthopedic and trauma surgery. Transplantation of autologous muscle precursor cells has produced encouraging results but is associated with significant donor site morbidity. In contrast to this approach, bone marrow-derived (BMD) cells can be derived without functional deficits. Thus, we examined whether regular muscle regeneration could be improved by local application of autologous BMD cells in a rat model of blunt skeletal muscle trauma (13).

One week after standardized open blunt crush injury to the left soleus muscle, 106 autologous BMD cells were injected into the traumatized muscle of male Sprague-Dawley rats. Rats of the control group received an equivalent volume of saline solution. Three weeks after treatment, the fast-twitch and tetanic contraction capacities of the soleus muscle were measured bilaterally by stimulating the sciatic nerves (13).

Contraction forces of soleus muscles in control animals recovered to 39% ± 10% (tetanic) and 59% ± 12% (fast-twitch) of the contralateral noninjured soleus muscle (P < 0.001). In contrast, autologous BMD cell injection restored contractile forces to 53% ± 8% (tetanic) and 72% ± 13% (fast-twitch) compared with those observed in contralateral noninjured soleus muscles. Thus, muscle function was significantly increased by BMD cell treatment (tetanic, P = 0.014; fast-twitch, P = 0.05). The autologous BMD cell grafting led to an increase in contraction force, 14% in tetanic and 13% in fast-twitch stimulation, demonstrating its potential to improve the functional outcome after skeletal muscle crush injury. The results demonstrate that local application of BMD cells significantly improves contraction force in response to a blunt trauma of skeletal muscle.

The tetanic contraction forces of uninjured control soleus muscles (1.32N ± 0.37N) were comparable to values given by previous studies (1.78N) (1). This value was reduced to 39% ± 10% (P < 0.001) of the control muscle, indicating a high standardization and reproducibility of the trauma model (13). Furthermore, all muscles showed a reduction of contraction force by repeated tetanic stimulations in contrast to fast-twitch stimulations, which points to a rapid consumption of local energy reservoirs. The nutritive conditions of the muscle in turn determine the time needed to allow the myocyte energy sources to recover. Thus, the nutritional state of the soleus muscle is represented by the gradient of tetanic contraction force reduction. Our results demonstrate that this gradient neither depends on injury nor is it influenced by cell therapy. All muscles showed a similar gradient of 4% loss per contraction without difference between the treated, untreated, and uninjured muscles. From these findings, it was concluded that nutrition is not the limiting factor in muscle healing - rather force loss seems to correlate with the number of myocytes capable for contraction. This highlights the necessity for sufficient microcirculation after blunt injury, so that the number of functional contractile elements is maximized. This conclusion was supported by the close correlation between fast-twitch and tetanic contraction force for the injured and control muscles. Although there was a linear correlation between twitch and tetanic forces, the gradient of force loss was different for twitch and tetanic contractions. The gradient between twitch and tetanic force indicates the percentage of recruitable contractile elements. Control muscles without injury had a significantly greater amount of recruitable myofibrils (90%) compared with injured muscles (30%), possibly reflecting early activation of contractile myocytes after injury for partial compensation of functional deficits. In BMD cell-treated muscles, the amount of myocytes activated by fast-twitch stimulation is 60% higher, leading to a reduced reservoir of silent contractile elements. The fact that BMD cell therapy did not influence these values argues for the failure of transplanted BMD cells to improve innervation of muscle fibers by neurogenic differentiation (13).

In conclusion, the results of this study suggest that the number of contractile elements is the limiting factor for the function of a bluntly injured skeletal muscle. These findings underscore the need for improving functional regeneration by local application of precursor cells capable of differentiating into myocytes. From a clinical perspective, these findings may have therapeutic implications, as donor site morbidity for BMD treatment is negligible, restoration of posttraumatic muscle performance is improved, and both rehabilitation and hospitalization times could be reduced.

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SUMMARY AND CONCLUSIONS

Clinical and experimental evidence suggests that the difficulty in the treatment of complex musculoskeletal injuries, as exemplified by fractures with severe open or closed soft tissue trauma, is related to the damage of soft tissues and, to a lesser degree, to the injury of the bone. Concomitant soft tissue trauma plays a pivotal role in the treatment of complex injuries as it guides fracture management, influences bone healing, and dictates patient prognosis. Extensive soft tissue injury and associated functional deficits frequently precede delayed fracture repair, possibly leading to nonunion and long-term skeletal muscle dysfunction. Furthermore, poor soft tissue management or muscular balance during reconstructive surgery or joint replacement may have detrimental consequences for joint function and may lead to lasting pain. At present, these problems are not solved. Apart from a few classification systems and scores, clinical management and reconstruction of soft tissues after trauma rely exclusively on empirical evidence.

In this review, we have tried to focus on the clinical relevance of findings from musculoskeletal injury research and the identification of pathways in which these results may affect clinical practice, functional understanding, and teaching. From both a research and a clinical perspective, skeletal muscles and bones must be considered as a functional unit with biological and mechanical interactions at many levels, such as vascular supply, mechanical stability, and cellular exchange (Fig. 3). Only a comprehensive view of the biomechanical, vascular, and cellular aspects of the musculoskeletal system will help in the understanding of fundamental mechanisms of soft tissue regeneration. We hope that the results discussed here and those of similar studies in the future will help in the understanding of key elements of the regeneration process, stimulate the healing of musculoskeletal tissues, and improve patient management and care.

Figure 3

Figure 3

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Acknowledgments

This work was supported by the Bundesministerium für Bildung und Forschung (BMBF, Federal Ministry of Education and Research) excellence cluster Berlin-Brandenburg Center for Regenerative Therapies (BCRT), and the German Research Foundation (DFG SFB 760).

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Keywords:

mechanobiology; regenerative stimuli; skeletal system; muscle and bone trauma; musculoskeletal regeneration

©2008 The American College of Sports Medicine